Project Summary It is becoming increasingly evident that the spinal circuitries below a paralyzing injury have a functional potential that far exceeds what has been thought to be possible. From recent studies in mice and rats with motor complete paralysis we know that the lumbosacral spinal cord can be neuromodulated electrically (eEmc) and pharmacologically (fEmc) to enable motor control, including full weight-bearing stepping. The main goal of the project is the development of noninvasive multiple neuromodulatory strategies to facilitate full weight bearing overground stepping in paralyzed subjects. Recently we demonstrated that four chronic, completely paralyzed individuals regained the ability to stand independently and the ability to voluntarily flex the hip, knee, and ankle when being stimulated epidurally. We propose to accomplish similar outcomes using a novel noninvasive multi-site spinal cord stimulation strategy in concert with pharmacological modulation with stand and step training to neuromodulate the lumbosacral circuitry so that completely paralyzed individuals can regain some locomotor function as well as voluntary movements. We propose to develop these strategies further by combining these interventions with an exoskeleton technology so that individuals with complete paralysis can regain significant levels of community mobility. We will determine the effectiveness of noninvasive spinal stimulation and administration of buspirone (a monoaminergic agonist) treatment for facilitating of locomotor activity in the gravity-neutral apparatus, body weight supported stepping on a treadmill, and stepping in the EKSO robotic device to achieve full weight bearing stepping in paralyzed subjects in rolling walker. It is anticipated that the early stages of development of this technology could be available within the clinic to improve motor function within a matter of a few years. These interventions have the potential to improve health, and can impact the quality of life and, in many cases, can likely to lead to reduced health costs and a lower burden not only to the paralyzed individuals, but also to their families and caregivers.